Over the past years gelatin capsules have gained an increasing share of the drug market and this tendency is still increasing. This development has lead to an increase in encapsulated medicaments which must be resistant to gastric juices and are only intended to release their content in the small intestine.
The demands placed on these gastric juice resistant capsules which are soluble in the intestine are becoming increasingly specific: after passing through the stomach, the drug is intended to decompose as rapidly as possible, preferably in the upper part of the duodenum and the active substance is released at the point of maximum reabsorption or of maximum efficiency.
Previously, the gelatin capsules were rendered resistant to gastric juices by treating them with formaldehyde which was caused to react with the gelatin either in gaseous form or in an aqueous solution or in solution with water miscible organic solvents.
It is generally known that the "hardened" gastric juice resistant gelatin capsules produced in this way were unable to withstand strict tests. It is very difficult to adjust the correct level of "hardening." It is also known that the gastric juice resistance and, in particular, the intestinal solubility of the gelatin capsules treated with formaldehyde tended to change in the course of time.
In addition, the intestinal solubility of the gelatin capsules treated with formaldehyde depends on the content of digestive ferments in the intestinal juice and, in particular, on pancreatin, thus causing many difficulties when these were prescribed for people with insufficient digestion.
For these reasons, processes and substances have been developed over the years for applying gastric juice resistant, intestinally soluble coatings to gelatin capsules and to tablets and dragees. The dissolution of these coatings was then exclusively dependent on the pH value of the digestive juices and not on the ferments.
The disadvantage of using the known gastric juice resistant, intestinally soluble, film forming substances such as shellac or celluloseacetate phthalate (CAP) or hydroxypropylmethylcellulose phthalate (HPMCP) or alkyl-half ester of ethylene-maleic acid anhydride co-polymerizates or alkyl half ester of vinylmethylethylmaleic acid anhydride co-polymerizates (see German AS 14 67 875, published Jan. 23, 1969), is that it is necessary to use toxic and/or inflammable solvents or solvent mixtures for producing the lacquer solutions. In addition, shellac and CAP are subject, during storage, to changes in their solubility in intestinal juice in terms of delaying of the dissolution rate of the coated drug blank which in the case of CAP can also be associated with the separating off of acetic acid.
Although the coating of tablets and dragees or dragee cores with gastric juice resistant, intestinally soluble solvent laquers can be effected relatively easily by the known processes owing to their porous surfaces which facilitate adherence of the lacquers, difficulties arise when coating gelatin capsules, for example, with CAP or HPMCP owing to their smooth, non-absorptive surfaces. In particular, these difficulties involve the adhesion of the lacquer and the smoothness, brilliance and transparency of the film of lacquer.
Owing to the need for safe processing and in view of the increasingly stricter environmental protection regulations, efforts were made to obtain gastric juice resistant, intestinally soluble lacquer substances which avoid the need to use toxic and/or inflammable solvents. In the course of research, a gastric juice resistant, intestinally soluble lacquer in the form of an aqueous dispersion of the anionic polymerizate of methacrylic acid and acrylic acid esters, for example, methacrylic acid- acrylic acid ethylester 50:50 copolymerizate = MAC, was found. This is described in German OS 21 35 073, laid open Feb. 1, 1973 and will be referred to hereafter by the abbreviation MAC.
This aqueous dispersion of MAC can easily be applied to medicinal blanks by the known air suspending technique, (for example, Glatt or Glatt-Wurster). However, if this MAC film is applied to gelatin capsules, the gelatin shell becomes so brittle during the subsequent drying process that it decomposes when only slight pressure is applied thereto. Thus the gelatin capsules lose their mechanical stability when they are treated with an aqueous MAC dispersion.
It is not exactly known which mechanism causes this embrittlement. The highly acidic submicroscopic MAC dispersion particles possibly penetrate the gelatin shell and cause the embrittlement therein. It was then found that this embrittlement of the gelatin capsules can be avoided by applying a neutralizing layer between the gelatin shell and the MAC film. This neutralizing layer prevents the penetration into the gelatin shell of the highly acidic submicroscopic dispersion particles.
The term "gelatin capsules" as used in this test is intended to refer both to hard and also soft gelatin capsules.
In German OS 19 24 647, laid open Nov. 19, 1970, it is disclosed that to produce carriagable and storable gastric juice resistant, intestinally soluble capsules, it is possible to spray on a priming lacquer consisting of one or more film forming colloids which are totally or partially soluble both in water and organic solvents and thereafter coating the capsules which have been pretreated in this way with a gastric juice resistant lacquer.
Similarly, a process is disclosed in GB patent 1 190 387, issued May 6, 1970 for producing gastric juice resistant hard gelatin capsules by applying to the gelatin capsules an inner layer of polyvinylpyrrolidone and an outer layer of celluloseacetatephthalate (CAP).
In both cases, it is necessary to use toxic and/or inflammable solvents to dissolve the gastric juice resistant lacquers in question.
The following substances, inter alia, were tested in the course of efforts to find suitable film forming substances which prevent the gelatin shells of the capsules from becoming brittle: reemulsifiable vinylacetate polymers and vinylacetate co-polymers, polyvinylacetate, polyvinylalcohols, polyvinylpyrrolidone, dextrine, modified starches, gum arabic, shellac and cationic polymerizates of di-loweralkyl-amino-lower alkyl-methacrylate with other neutral methacrylic acid esters in aqueous dispersions, in aqueous, aqueous-ammoniacal, aqueous-alcoholic or alcoholic solutions with or without the common physiologically acceptable plasticizers.